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CADASIL

Maladywise

Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy

Fact Sheet

Genetics

  • Error in the NOTCH3 Gene on Chromosome 19. This gene is responsible for the development of smooth muscle in the walls of blood vessels.

Cause

  • Although CADASIL affects all blood vessels, the complications are largely limited to the long penetrating arteries of the brain. The blood-brain barrier is also affected.

Pathology

  • Autopsies of brains with CADASIL show lacunar infarcts (strokes deep in the brain in the pons, thalamus and brain stem).

Incidence

  • The rate of disease-causing variants however is somewhere between 1 to 5 in 100,000 people. The prevalence of all NOTCH3 gene variants might be as high as 1 in 300 people.

Onset

  • Early adulthood but some cases reported in children and adolescents

Clinical Features

CADASIL usually presents with one or more of:

  • Migraine with aura

    • Occurs in 50% of patients, usually the first sign, more common in women

    • The average age is 30 years

    • Aura usually involves the visual and sensory systems (flashing lights) but 50% have other symptoms as well including hemiplegia, confusion, and hallucinations)

  • Acute reversible encephalopathy

    • Occurs in 10% of patients

    • Manifests as altered consciousness, hallucinations, seizures, weakness, numbness, loss of speech

    • Usually the symptoms that leads to a diagnosis

  • Ischemic episodes

    • Strokes and Transient Ischaemic Attacks (Mini strokes)

    • Occurs in 85% of patients, the median age is 52 years

    • Usually a classic lacunar stroke syndrome (Pure motor or sensory symptoms, Hemiparesis, Ataxia-hemiparesis, Dysarthria-clumsy hand syndrome, Sensorimotor stroke)

  • Cognitive impairment and dementia

    • Occur in 60% of patients

    • Lacunar lesions and global brain atrophy on MRI

    • Usually slow cognitive decline

  • Psychiatric disturbances

    • Mood disorders occur in 25 %of patients

    • Commonly moderate depression, sometimes bipolar, panic disorder, hallucinations or delusions

    • Apathy is a common symptom, more common in men

  • Seizures

    • Occur in 5 to 10% of patients

Evaluation

  • Suspect CADASIL when classical symptoms present, particularly when there is a positive family history of stroke or dementia, or when there are typical findings on brain MRI. A lack of family history doesn’t exclude a diagnosis.

History and Examination

  • Thorough standard history with a focus on a family history of stroke, migraine, mood disorders, seizures and dementia. Detailed neurological examination documenting all findings.

Imaging

  • MRI brain for all patients with suspected CADASIL.

  • MRI usually shows recent lacunar infarcts, chronic lacunes, and white matter hyperintensities.

  • There are also temporal lobe and external capsule hyperintensities, subcortical lacunar lesions, cerebral microbleeds and brain atrophy.

Diagnosis

  • Either genetic analysis or if not available or conclusive, then skin biopsy looking for characteristic changes.

Differentials

  • Acquired Disorders such as small vessel disease, multiple sclerosis, and PACNS (primary angiitis of the central nervous system)

  • Inherited Disorders such as Fabry disease, CARASIL, and leukodystrophy.

Management

  • There is currently no specific disease-modifying treatment for CADASIL :(

Acute Stroke

  • Managed as you normally would. No evidence systemic thrombolysis improves outcomes after a small vessel stroke in CADASIL but if the stroke is in the territory of a thromboembolic large vessel then it can be considered.

Secondary Stroke Prevention

  • Control hypertension

  • Statin therapy if high blood cholesterol

  • Glucose control if Diabetic

  • Antiplatelet therapy such as low-dose Aspirin 100mg daily

  • Smoking cessation

  • Limit alcohol consumptions

  • Weight control

  • Regular aerobic exercise

  • A Mediterranean diet that is rich in fruits, vegetables, grains, nuts, fish and low-fat dairy.

Symptomatic Therapy

  • Doneprezil in patients with slowed executive function and processing speed

  • SSRI for emotional lability in pseudobulbar palsy

  • Migraine attacks are treated with NSAIDs. Triptans are contraindicated.

Prognosis

  • Migraine with aura around age 30.

  • Strokes, TIAs and mood disorders from age 40 to 60.

  • Dementia between ages 50 and 60

  • Gait difficulty at age 60

  • Can be highly variable with some patients being completely asymptomatic until their seventies

  • Early onset doesn't necessarily mean rapid progression

Life Expectancy

  • The average life expectancy is 65 years for men and 70 years for women.

References

Fact Sheet